This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Objective: To use live-attenuated SIV vaccines as a unique opportunity to study effective anti-immunodeficiency virus immune responses. We vaccinated 8 rhesus macaques with the live-attenuated SIV strain SIVmac239[unreadable]nef in the spring of 2009. We monitored the development of SIV-specific immune responses in this cohort using a variety of assays. The vaccinated animals, along with eight naive controls, were challenged intrarectally (i.r.) with repeated, low doses of the uncloned "swarm" virus SIVsmE660 in the fall of 2009. Surprisingly, vaccinated macaques significantly delayed acquisition of SIVsmE660. After five mucosal challenges with 6x106 vRNA copies of SIVsmE660 we detected replication of the challenge strain in only four of the eight vaccinated animals. In contrast, 7 of the 8 control animals became infected with SIVsmE660 after these five challenges. Importantly, the SIVsmE660-infected vaccinated animals controlled peak acute virus replication significantly better than the naive controls. Three of the four vaccinees rapidly brought virus replication under control by week 4 post-infection. These results suggest that a well-designed HIV vaccine might both reduce the rate of acquisition and control viral replication during the acute phase of infection. The research uses WNPRC Immunogenetics &Virology Services.